1. Field of the Invention
The present invention relates to the field of pharmacochemistry, and more particularly to optically active 2-hydroxytetrahydrothienopyridine derivatives, preparation method and use thereof in the manufacture of a medicament, especially for preventing or treating thrombosis and embolism related diseases.
2. Description of the Related Art
Clopidogrel is an anti-platelet aggregation agent that is most widely used all over the world at present, and used for treating atherosclerosis, acute coronary syndrome (ACS), thrombotic complications, and other diseases in clinic. Clinical tests in many years have demonstrated the efficacy and safety of clopidogrel for thrombotic cardio-cerebrovascular diseases (Lancet, 1996, 348: 1329). Clopidogrel is a precursor drug, which is metabolized in vivo through two oxidative steps by the liver P450 enzyme system to generate an active metabolite, which is covalently bound to P2Y12 receptor on the platelet surface to inhibit platelet aggregation through P2Y12 receptor antagonism (Thromb Haemost, 2000, 84: 891). However, the researches on in-vivo metabolism of clopidogrel reveal that 85% of the prototype drug is hydrolyzed by human carboxylesterase 1 (hCE1) in the liver into an inactive carboxylic derivative of clopidogrel (J Pharmacol Exp Ther, 2006, 319: 1467), which greatly reduces the oral bioavailability of clopidogrel, resulting in the disadvantages of clopidogrel such as high dosage in clinical use (load dosage: 300 mg clopidogrel), slow onset of action, and delayed inhibition of platelets (Cardiovascular Drug Reviews, 1993, 11: 180). In addition, due to the differential expression of the P450 enzyme system in the liver among different individuals, clopidogrel that functions by metabolism by the P450 enzyme system has significant individual differences in clinical efficacy, including, for example, the presence of “clopidogrel resistance”, and occurrence of cardiovascular events including stent thrombosis (ST) (Circulation, 2004, 109: 166).
Prasugrel, a new anti-platelet agent, is developed by Sankyo Pharmaceuticals Co., Ltd. and Eli Lilly Company. Compared with clopidogrel, prasugrel can more quickly and effectively inhibit platelet aggregation, but has a higher risk of bleeding. In elective percutaneous coronary intervention (PCI) for treating acute coronary syndrome, compared with clopidogrel, prasugrel can significantly lower the incidence of ischemic events (including stent thrombosis), but the bleeding risk is increased (N Engl J Med, 2007, 357: 2001). Other adverse effects of prasugrel include, for example, thrombocytopenia and neutropenia.
Certain 2-hydroxytetrahydrothienopyridine derivatives having anti-platelet aggregation effect are disclosed in U.S. Pat. Nos. 5,190,938, 5,874,581, and WO9749397. These compounds are, however, racemic mixtures, and to date, there have been no studies proving whether their racemates and enantiomers are different in efficacy and safety. In Chinese Patent Application No. 200810097756.7, certain aromatic heterocyclic carboxylate ester derivatives of prasugrel and clopidogrel, especially certain racemic derivatives of prasugrel, are disclosed, but optically active alkyl carboxylate derivatives and other related derivatives of 2-hydroxytetrahydrothienopyridine are not involved.
Therefore, there is a need in clinic for development of a new anti-platelet aggregation agent that has a rapid onset of action and high efficacy, and can avoid the bleeding side effect.